rs7671781

chr4-168512176-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001166108.2(PALLD):c.672G>A(p.Met224Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,613,202 control chromosomes in the GnomAD database, including 78,961 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M224T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.29 (6561 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72400 hom.)
• Consequence: PALLD NM_001166108.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.94

Genes affected

PALLD (HGNC:17068): (palladin, cytoskeletal associated protein) This gene encodes a cytoskeletal protein that is required for organizing the actin cytoskeleton. The protein is a component of actin-containing microfilaments, and it is involved in the control of cell shape, adhesion, and contraction. Polymorphisms in this gene are associated with a susceptibility to pancreatic cancer type 1, and also with a risk for myocardial infarction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

LOC107986198 (HGNC:):

DDX60L (HGNC:26429): (DExD/H-box 60 like) This gene encodes a member of the DExD/H-box helicase family of proteins, a subset of the super family 2 helicases. Members of the DExD/H-box helicase family share a conserved functional core comprised of two RecA-like globular domains. These domains contain conserved motifs that mediate ATP binding, ATP hydrolysis, nucleic acid binding, and RNA unwinding. In addition to functions in RNA metabolism, members of this family are involved in anti-viral immunity and act as cytosolic sensors of viral nucleic acids. The protein encoded by this gene has been shown to inhibit hepatitis C virus replication in response to interferon stimulation in cell culture. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010214746).
• BP6: Variant 4-168512176-G-A is Benign according to our data. Variant chr4-168512176-G-A is described in ClinVar as [Benign]. Clinvar id is 403285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALLD	NM_001166108.2	c.672G>A	p.Met224Ile	missense_variant	2/22	ENST00000505667.6
LOC107986198	XR_001741448.3	n.280+18385C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALLD	ENST00000505667.6	c.672G>A	p.Met224Ile	missense_variant	2/22	1	NM_001166108.2	A2

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44444 AN: 151670 Hom.: 6556 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.280

GnomAD3 exomes AF: 0.281 AC: 70311 AN: 250460 Hom.: 10540 AF XY: 0.282 AC XY: 38208 AN XY: 135350

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.176

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.294

GnomAD4 exome AF: 0.311 AC: 454076 AN: 1461412 Hom.: 72400 Cov.: 38 AF XY: 0.309 AC XY: 224372 AN XY: 727018

Gnomad4 AFR exome AF: 0.244

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.194

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.393

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.297

GnomAD4 genome AF: 0.293 AC: 44463 AN: 151790 Hom.: 6561 Cov.: 32 AF XY: 0.292 AC XY: 21619 AN XY: 74134

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.276

Alfa AF: 0.307 Hom.: 5209

Bravo AF: 0.280

TwinsUK AF: 0.309 AC: 1147

ALSPAC AF: 0.333 AC: 1284

ESP6500AA AF: 0.242 AC: 1065

ESP6500EA AF: 0.305 AC: 2624

ExAC AF: 0.285 AC: 34602

Asia WGS AF: 0.196 AC: 683 AN: 3478

EpiCase AF: 0.319

EpiControl AF: 0.315

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2020	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Pancreatic cancer, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.0020
Dann	Benign	0.80
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.19	T;T;T
MetaRNN	Benign	0.0010	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.090	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.49	T;T;T
Vest4		0.030
MutPred		0.19		Gain of glycosylation at S220 (P = 0.0087);Gain of glycosylation at S220 (P = 0.0087);.;
MPC		0.22
ClinPred		0.014	T
GERP RS		-11
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7671781; hg19: chr4-169433327; COSMIC: COSV54981267; COSMIC: COSV54981267;